Affinage

MAPK3

Mitogen-activated protein kinase 3 · UniProt P27361

Length
379 aa
Mass
43.1 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAPK3 (ERK1) is a dual-specificity-regulated proline-directed serine/threonine kinase that serves as a terminal effector of the Raf→MEK→ERK mitogenic cascade, converting growth factor and integrin signals into proliferative and developmental gene-expression programs (PMID:1717989, PMID:1372523, PMID:1603090, PMID:7814385, PMID:8702807). Its catalytic activation requires dual phosphorylation on tyrosine and threonine by MAP kinase kinase (MEK), and it can autophosphorylate on tyrosine; activity is reversed by serine/threonine and tyrosine phosphatases (PMID:1717989, PMID:7687743). A defining feature is that the sustained, late phase of activation—not the transient early phase—is coupled to nuclear translocation throughout G1 and is specifically required for passage through the restriction point, induction of cyclin D1, and DNA synthesis (PMID:8394845, PMID:8380983, PMID:7775600, PMID:8702807). In the nucleus and cytoplasm ERK1 phosphorylates a defined set of substrates including the transcriptional machinery via ELK1 and immediate-early gene programs (Egr1, c-Fos, the Integrator subunit INTS11), the cytoskeletal protein MAP2c, the pro-apoptotic regulator Bad, sphingosine kinase 1 (Ser225), and components of receptor feedback (FGFR1/FRS2) (PMID:14532121, PMID:25401279, PMID:28982763, PMID:29259132, PMID:9453550, PMID:19777442). ERK1 embeds itself in multiple negative-feedback loops—directly phosphorylating and stabilizing the dual-specificity phosphatases MKP-1/MKP-2, attenuating FGFR1/FRS2 signaling, and transcriptionally and post-translationally tuning MEK1/2 levels (PMID:8995446, PMID:10617468, PMID:26163823, PMID:31013829). Its kinase output is further set by reversible post-translational modification: acetylation by CBP/p300 reversed by HDAC6 deacetylation at Lys-72, SUV420H1-mediated methylation at Lys-302/361, and inhibitory S-nitrosylation at Cys183 (PMID:29259132, PMID:26586479, PMID:29286066). In vivo, ERK1 functions largely redundantly with ERK2, with total ERK activity rather than isoform identity being the determinant of proliferation and development, while ERK1-selective roles emerge in osteoclast/HSC-niche and arteriogenic contexts (PMID:19242111, PMID:26235619, PMID:22303456); genetic studies establish requirements in T-cell positive selection, ovarian follicle activation, ovulation and luteinization, chondrocyte terminal differentiation, and maintenance of endothelial identity against TGFβ-driven EndMT (PMID:16226508, PMID:19443782, PMID:20237411, PMID:25401279, PMID:25803847, PMID:28218391, PMID:31196980).

Mechanistic history

Synthesis pass · year-by-year structured walk · 29 steps
  1. 1991 High

    Established ERK1 as a bona fide serine/threonine kinase whose activity depends on phosphorylation state and which can relay signal to downstream kinases, defining it as an enzyme in a cascade.

    Evidence Bacterial expression of mouse Erk-1 with in vitro kinase, phosphatase treatment, and S6KII reactivation assays

    PMID:1717989

    Open questions at the time
    • Physiological upstream activator not yet identified
    • In vitro autophosphorylation may not reflect cellular activation mechanism
  2. 1992 High

    Showed that ERK1 activation by growth factors is biphasic and that the sustained late phase, not transient activation, correlates with mitogenic outcome—linking activation kinetics to cell fate.

    Evidence Epitope-tagged ERK1 in fibroblasts, in vitro MBP kinase assays, phosphoamino acid analysis across multiple growth factors

    PMID:1372523 PMID:1603090

    Open questions at the time
    • Molecular basis for sustained vs transient kinetics unresolved
    • Nuclear vs cytoplasmic activity not yet separated
  3. 1993 High

    Demonstrated ERK1/2 are causally required for growth-factor-driven proliferation and gene transcription, moving beyond correlation to functional necessity.

    Evidence Antisense knockdown and dominant-negative (T192A/Y194F) mutants with reporter and growth assays in fibroblasts

    PMID:8397401

    Open questions at the time
    • Direct transcriptional targets not defined here
    • ERK1 vs ERK2 contributions not separated
  4. 1993 High

    Defined the regulated nuclear translocation of ERK1/2 as mitogen-specific and persistent through G1, while the upstream activator stays cytoplasmic—establishing spatial control of signaling output.

    Evidence Immunofluorescence, tagged-construct transfection, and subcellular fractionation in stimulated cells

    PMID:8394845

    Open questions at the time
    • Translocation machinery/NLS-like determinants not identified
    • Nuclear substrates not yet enumerated
  5. 1993 High

    Resolved the activation mechanism biochemically—autophosphorylation at Tyr-204, differential phosphatase sensitivity, and MEK acting mainly via tyrosine phosphorylation.

    Evidence GST-ERK1 in vitro kinase assays, CD45/PP2A treatment, K71A mutagenesis, and MEK activation

    PMID:7687743

    Open questions at the time
    • Relative in vivo contribution of autophosphorylation vs MEK unclear
    • p56lck phosphorylation physiological relevance untested
  6. 1995 Medium

    Connected ERK1 activation to upstream adhesion and cytoskeletal context, showing integrin ligation activates ERK1 in an actin-dependent manner.

    Evidence Integrin cross-linking/fibronectin adhesion with IP kinase assays and cytochalasin D disruption

    PMID:7814385

    Open questions at the time
    • Mechanism linking actin to ERK activation undefined
    • Single-lab pharmacological perturbation
  7. 1995 High

    Tied sustained ERK1/2 activity to the cell-cycle restriction point, defining its temporal window of action during G1.

    Evidence Cell-cycle synchronization with IP kinase and CDK2 assays

    PMID:7775600

    Open questions at the time
    • Direct G1 effector substrates not identified in this study
  8. 1996 High

    Identified cyclin D1 as a key transcriptional output coupling sustained ERK activity to G1 progression, providing a mechanistic effector for the restriction-point requirement.

    Evidence Dominant-negative/constitutively active MKK1 and kinase-dead ERK, MKP-1, and Raf-ER chimera with cyclin D1 promoter reporters

    PMID:8702807

    Open questions at the time
    • Direct transcription factors at the cyclin D1 promoter not pinpointed here
  9. 1997 High

    Revealed that the ERK cascade induces its own negative regulators (MKP-1/MKP-2), establishing transcriptional feedback control of pathway duration.

    Evidence Constitutively active MKK1/v-ras, PD098059 inhibition, and Raf-ER chimera with phosphatase immunoblots

    PMID:8995446

    Open questions at the time
    • Transcription factors mediating MKP induction not defined
  10. 1999 High

    Showed ERK1/2 directly phosphorylates and stabilizes MKP-1, adding a post-translational layer to feedback that shapes signal duration without altering phosphatase activity.

    Evidence In vitro kinase assay, Ser359/Ser364 mutagenesis, pulse-chase stability, and proteasome inhibition

    PMID:10617468

    Open questions at the time
    • The ubiquitin ligase targeting MKP-1 not identified
  11. 1998 Medium

    Demonstrated that the subcellular location of activated ERK in vivo dictates which substrate class (cytoplasmic MAP2c vs nuclear c-Fos) is phosphorylated, linking localization to functional specificity in neurons.

    Evidence In vivo electroconvulsive shock with phospho-MAPK immunohistochemistry and PD098059 inhibition across neuron types

    PMID:9453550

    Open questions at the time
    • Determinants of region-specific localization unknown
    • Single-lab correlative localization
  12. 2003 High

    Added SphK1 as a direct ERK1/2 substrate, coupling ERK activity to sphingolipid signaling and membrane translocation of an effector enzyme.

    Evidence In vitro kinase assay, Ser225 mutagenesis, subcellular fractionation, and enzyme activity assays

    PMID:14532121

    Open questions at the time
    • Physiological contexts of SphK1 activation by ERK1 not delineated
  13. 2005 High

    Established an in vivo developmental requirement for ERK1/2 in T-cell positive selection, distinguishing proliferation-linked from differentiation-linked activity.

    Evidence Erk1 and Erk2 knockout mice with flow cytometric thymocyte analysis

    PMID:16226508

    Open questions at the time
    • Substrate basis for selection vs differentiation distinction unresolved
  14. 2009 High

    Defined an ovarian ERK1/2 program where C/EBPβ is the critical transcriptional mediator for LH-induced ovulation and luteinization, mapping a tissue-specific effector.

    Evidence Granulosa-cell conditional Erk1/Erk2 and Cebpb knockouts with in vivo ovulation assays

    PMID:19443782

    Open questions at the time
    • Direct ERK1/2 substrates upstream of C/EBPβ not identified
  15. 2009 Medium

    Showed ERK1 kinase activity is anti-apoptotic via Bad phosphorylation and suppression of Bax/cytochrome c release, placing ERK1 on the intrinsic mitochondrial survival axis.

    Evidence ERK1 and kinase-dead K71R overexpression in HeLa with Bad/Bax/cytochrome c immunoblots and death assays

    PMID:19777442

    Open questions at the time
    • Direct vs indirect Bad phosphorylation by ERK1 not fully resolved
    • Single-lab overexpression system
  16. 2009 Medium

    Tested whether ERK1 vs ERK2 functional differences reflect isoform identity, concluding total ERK activity (driven by expression level) governs proliferation.

    Evidence Single and combined ERK1/ERK2 siRNA silencing with proliferation and expression analysis

    PMID:19242111

    Open questions at the time
    • Single primary method (siRNA)
    • Contexts with genuine isoform-specific roles not excluded
  17. 2010 High

    Identified an ERK1/2–Akt1 crosstalk node controlling arterial morphogenesis, with constitutively active ERK1/2 sufficient to rescue arteriogenesis defects.

    Evidence Synectin-deficient mice/zebrafish, Akt isoform knockdowns, and constitutively active ERK1/2 rescue in endothelium

    PMID:20237411

    Open questions at the time
    • Endothelial ERK substrates driving arteriogenesis unmapped
  18. 2015 High

    Established genetically that ERK1 and ERK2 are functionally redundant in development and that transgenic ERK1 rescues ERK2 loss—total activity, not isoform, sets developmental outcome.

    Evidence Mouse Erk1/Erk2 allelic series with transgenic ERK1 rescue and developmental scoring

    PMID:26235619

    Open questions at the time
    • Tissue contexts with non-redundant roles not fully enumerated
  19. 2015 High

    Mapped a chondrocyte terminal-differentiation program in which ERK1/2 acts through Egr1/Egr2 to control Osteopontin and Mmp13 expression.

    Evidence Osx-Cre conditional Erk1/2 knockout with histology, in situ hybridization, and Osteopontin promoter reporters

    PMID:25401279

    Open questions at the time
    • Direct ERK phosphorylation events upstream of Egr1/Egr2 not shown
  20. 2015 Medium

    Revealed an ERK1-selective role in regulating the HSC niche via M-CSFR-dependent osteoclastogenesis, indicating isoform-specific functions in myeloid/bone biology.

    Evidence ERK1 knockout mice, bone-marrow transplantation, flow cytometry, and osteoclastogenesis assays

    PMID:22303456

    Open questions at the time
    • Mechanism linking ERK1 to M-CSFR expression undefined
    • Single-lab study
  21. 2015 Medium

    Added a methylation layer of ERK1 regulation, showing SUV420H1 trimethylates Lys-302/361 to sustain ERK1 phosphorylation and expression.

    Evidence In vitro methylation, K302/K361 mutagenesis, and SUV420H1 knockdown with immunoblot/qRT-PCR

    PMID:26586479

    Open questions at the time
    • Mechanism by which methylation affects phosphorylation/transcript unclear
    • Single-lab
  22. 2015 Medium

    Demonstrated ERK1/2 feedback regulation of upstream MEK by oppositely controlling MEK1 (transcriptionally up) and MEK2 (proteasomally down), refining cascade homeostasis.

    Evidence ΔRaf-1:ER/B-Raf(V600E) systems, ERK siRNA, promoter/3'UTR reporters, and proteasome inhibitors

    PMID:26163823

    Open questions at the time
    • E3 ligase mediating MEK2 turnover not identified
    • Single-lab
  23. 2015 High

    Mapped the ovulation mechanism to ERK-driven Egr1 induction that activates the Ptgs2/COX-2 promoter, defining a direct transcriptional axis for fertility.

    Evidence In vivo PD0325901 inhibition, Egr1 ChIP at Ptgs2 promoter, and Egr1 siRNA in granulosa cells

    PMID:25803847

    Open questions at the time
    • Direct ERK substrate upstream of Egr1 not pinpointed
  24. 2017 Medium

    Connected ERK1/2 to primordial follicle activation via mTORC1-KITL signaling in pre-granulosa cells, broadening the ovarian role to earlier follicle stages.

    Evidence Ex vivo ovary culture with U0126 and immunoblot/immunofluorescence of mTORC1/Akt/Foxo3 markers

    PMID:28218391

    Open questions at the time
    • Direct ERK targets in the mTORC1-KITL axis unknown
    • Pharmacological inhibition only
  25. 2017 Medium

    Identified the Integrator catalytic subunit INTS11 as an ERK1/2 substrate and showed Integrator transduces ERK transcriptional responses at immediate-early genes and enhancers.

    Evidence ERK inhibition, ChIP-seq, Integrator depletion, and phosphorylation assays in cancer cells

    PMID:28982763

    Open questions at the time
    • Direct INTS11 phosphosites and their consequences not fully defined
    • Single-lab
  26. 2017 Medium

    Added inhibitory S-nitrosylation at Cys183 as a regulatory modification that suppresses ERK phosphorylation and promotes glioma apoptosis, linking NO signaling to ERK output.

    Evidence Biotin switch assay, C183A mutagenesis, apoptosis/viability assays, and human glioma tissue correlation

    PMID:29286066

    Open questions at the time
    • Mechanism by which Cys183 modification blocks activation loop phosphorylation unclear
    • Single-lab
  27. 2017 High

    Established acetylation/deacetylation control of ERK1 via CBP/p300 and HDAC6 at Lys-72, forming an ERK1–HDAC6 feed-forward loop that tunes kinase activity.

    Evidence Co-IP, HDAC6 knockdown, K72Q/K72R mutagenesis, in vitro ELK1 kinase assay, and mass spectrometry

    PMID:29259132

    Open questions at the time
    • In vivo physiological role of Lys-72 acetylation not established
  28. 2019 High

    Showed ERK1/2 is required in quiescent endothelium to suppress TGFβ-driven EndMT and maintain endothelial identity, extending ERK function beyond proliferation to tissue homeostasis.

    Evidence Endothelial conditional Erk2 knockout on Erk1-null background with fate mapping, RNA-seq, and HUVEC knockdown

    PMID:31196980

    Open questions at the time
    • Direct ERK substrates suppressing the TGFβ program not identified
  29. 2019 Medium

    Demonstrated ERK1/2 directly phosphorylates FGFR1 and FRS2 to dampen receptor tyrosine phosphorylation, defining a negative-feedback brake on FGF signaling with p38 crosstalk.

    Evidence Pharmacological ERK/p38 inhibition with phospho-Western blots in FGFR1-expressing cell lines

    PMID:31013829

    Open questions at the time
    • Specific FRS2/FGFR1 phosphosites and their direct effects partially defined
    • Single-lab pharmacology

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple post-translational modifications (acetylation, methylation, S-nitrosylation) integrate with MEK-driven activation-loop phosphorylation to set ERK1 output in vivo, and what distinguishes ERK1-selective contexts from redundant ones at the substrate level, remain unresolved.
  • No unified model linking PTM cross-regulation to physiological signaling
  • Substrate-level basis for ERK1-specific roles undefined
  • Determinants of localization-dependent substrate selection unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 4 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 5 R-HSA-1474165 Reproduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2
Partners
FGFR1FRS2HDAC6INTS11MAP2K1MKP-1/DUSP1SPHK1SUV420H1

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 Bacterially expressed mouse Erk-1 is an active serine/threonine kinase that also autophosphorylates on tyrosine; treatment with serine/threonine phosphatase 2A or tyrosine phosphatase 1B significantly decreased its kinase activity, and Erk-1 could reactivate ribosomal protein S6 kinase (S6KII) in vitro. Bacterial expression, in vitro kinase assay, phosphatase treatment, substrate reactivation assay Proceedings of the National Academy of Sciences of the United States of America High 1717989
1992 p44mapk (ERK1) is activated in a biphasic manner by growth factors (alpha-thrombin, PDGF, serum); activation requires dual phosphorylation on tyrosine and threonine, and the late/sustained phase of activation correlates strictly with mitogenic potential and DNA synthesis. Epitope-tagged expression in fibroblasts, in vitro kinase assay (myelin basic protein phosphorylation), phosphoamino acid analysis Molecular biology of the cell High 1372523 1603090
1993 Activation of p42mapk/p44mapk is required for growth factor-stimulated fibroblast proliferation and gene transcription; antisense reduction of p42/p44mapk expression (by ~90%) or overexpression of kinase-deficient mutants (T192A or Y194F) inhibited MAP kinase activation, collagenase promoter-driven transcription, and cell growth in proportion to the extent of MAP kinase inhibition. Antisense RNA expression, dominant-negative kinase mutant overexpression, reporter gene assay (CAT), cell growth assay Proceedings of the National Academy of Sciences of the United States of America High 8397401
1993 Upon mitogenic stimulation, p42mapk and p44mapk translocate from the cytoplasm into the nucleus rapidly (within 15 min) and persistently (throughout G1); this translocation is reversible, coupled to mitogenic potential, and does not occur with non-mitogenic stimuli. In contrast, the upstream activator p45mapkk remains cytoplasmic even during prolonged stimulation. Immunofluorescence with specific antibodies, transfection of epitope-tagged recombinant MAP kinases, subcellular fractionation, live cell imaging The Journal of cell biology High 8394845
1993 Human p44erk1 (ERK1) expressed as a GST fusion in E. coli autophosphorylates at the regulatory Tyr-204 (and additional sites); activity is strongly reduced by tyrosine phosphatase CD45 but not by serine/threonine phosphatase 2A; p56lck phosphorylates ERK1 at two autophosphorylation sites including Tyr-204; MAP kinase kinase (MEK) further activates ERK1 primarily through enhanced tyrosine phosphorylation. Bacterial expression (GST fusion), in vitro kinase assay (myelin basic protein substrate), phosphatase treatment, site-directed mutagenesis (K71A), MEK activation assay Molecular and cellular biology High 7687743
1993 The sustained (late) phase of p44mapk activation, but not the transient early phase, is specifically required for mitogenic signaling; pertussis toxin abolished the late phase and mitogenicity; non-mitogenic stimuli (thrombin-receptor peptide) induced only the early phase. Co-stimulation of FGF with TMP (a non-mitogenic agonist) synergistically potentiated late-phase p44mapk activation and DNA synthesis. In vitro kinase assay, pharmacological inhibition (pertussis toxin, hirudin), DNA synthesis assay (3H-thymidine incorporation) The Biochemical journal High 8380983
1995 Ligation of beta1 integrins (by fibronectin adhesion or antibody cross-linking) rapidly activates p44erk-1 and p42erk-2 through tyrosine phosphorylation; disruption of actin filaments with cytochalasin D completely abolishes this integrin-mediated MAP kinase activation, indicating actin cytoskeleton integrity is required. Cell adhesion assay, anti-integrin antibody cross-linking, immunoprecipitation kinase assay, cytochalasin D treatment, phosphotyrosine Western blot The Journal of biological chemistry Medium 7814385
1995 Sustained p42/p44MAPK (ERK1/2) activation during G1 phase is required to pass the restriction point; p44mapk and p42mapk activities are elevated throughout G1 and decline to negligible values at the G1/S transition, whereas CDK2 activity continues to rise through S phase. Cell cycle synchronization, immunoprecipitation kinase assay (MBP substrate), phosphoamino acid analysis, CDK2 activity assay Journal of cellular physiology High 7775600
1996 Persistent activation of p42/p44MAPK positively regulates cyclin D1 expression: dominant-negative MKK1, kinase-dead p44MAPK, or MKP-1 overexpression strongly inhibited cyclin D1 promoter activity and protein; constitutively active MKK1 increased cyclin D1 in a growth factor-independent manner; activation of the Raf→MKK1→p42/p44MAPK cascade alone (via DeltaRaf-1:ER chimera) was sufficient to fully induce cyclin D1. Co-transfection of dominant-negative and constitutively active constructs, reporter gene assay (cyclin D1 promoter-luciferase/CAT), Western blot, inducible Raf-ER chimera The Journal of biological chemistry High 8702807
1997 The p42/p44MAPK cascade induces expression of the dual-specificity phosphatases MKP-1 and MKP-2, forming a negative feedback loop; constitutively active MKK-1 or v-ras caused constitutive MKP-1/MKP-2 expression, and the MEK inhibitor PD098059 blocked both MAP kinase activation and MKP induction. Western blot with specific antibodies, dominant active/oncogenic constructs, pharmacological inhibition (PD098059), inducible DeltaRaf-1:ER chimera The Journal of biological chemistry High 8995446
1999 p42MAPK and p44MAPK directly phosphorylate MKP-1 on two C-terminal serine residues (Ser359 and Ser364) both in vivo and in vitro; this phosphorylation does not alter MKP-1's intrinsic phosphatase activity toward p44MAPK but stabilizes MKP-1 protein by attenuating ubiquitin-proteasome-mediated degradation. In vitro kinase assay, site-directed mutagenesis (Ser359/Ser364), ubiquitin-proteasome inhibitor experiments, pulse-chase protein stability assay, in vivo phosphorylation Science (New York, N.Y.) High 10617468
2003 ERK1/2 directly phosphorylates sphingosine kinase 1 (SphK1) at Ser225, activating its enzyme activity and inducing translocation from the cytosol to the plasma membrane; mutation of Ser225 abolishes agonist-mediated SphK1 activation and membrane translocation. In vitro kinase assay, site-directed mutagenesis (Ser225), subcellular fractionation, enzyme activity assay, multiple lines of evidence for ERK1/2 as the kinase The EMBO journal High 14532121
2005 ERK1 and ERK2 are both required for T cell positive selection in vivo; ERK1/2 activity is selectively retained during beta-selection-driven proliferation but is not required for completion of differentiation to the CD4+CD8+ preselection stage; ERK1/2 differentially affects CD4 vs. CD8 T cell maturation. Targeted gene deletion (Erk1 and Erk2 knockout mice), flow cytometry, thymocyte developmental analysis Immunity High 16226508
2009 ERK1/2 in granulosa cells are essential in vivo for LH-induced oocyte resumption of meiosis, ovulation, and luteinization; C/EBPbeta is a critical downstream transcriptional mediator of ERK1/2 activation in this pathway, as demonstrated by granulosa cell-specific disruption of Cebpb. Conditional knockout of Erk1 and Erk2 in mouse granulosa cells, genetic epistasis (Cebpb knockout), biochemical analyses, in vivo ovulation assay Science (New York, N.Y.) High 19443782
2009 Total ERK1/2 activity level (not isoform identity) is the key determinant for cell proliferation; combined single and double ERK1/ERK2 silencing showed that the apparent dominant role of ERK2 was due to its higher expression level, not isoform-specific function; ERK1 contribution is revealed when ERK2 activation is experimentally clamped. siRNA silencing of ERK1 and/or ERK2, cell proliferation assay, expression level analysis Cell cycle (Georgetown, Tex.) Medium 19242111
2010 ERK1/2 and Akt1 (but not Akt2) crosstalk regulates arterial morphogenesis; suppression of PI3K/Akt1 activity restores ERK1/2 activation and rescues arterial development defects in synectin-deficient mice and zebrafish; constitutively active ERK1/2 constructs in endothelial cells are sufficient to restore impaired arteriogenesis. Genetic knockouts (synectin-deficient mice), Akt1/Akt2-specific knockdowns, constitutively active ERK1/2 construct, in vivo and in vitro arterial morphogenesis assays, zebrafish knockdown The Journal of clinical investigation High 20237411
2015 ERK1 and ERK2 are functionally redundant during mouse development; total ERK1/2 activity level determines developmental outcome (placenta and embryo viability); transgenic expression of ERK1 fully rescues the embryonic and placental lethal phenotype caused by loss of ERK2. Genetic complementation in mice (multiple Erk1/Erk2 allele combinations), transgenic ERK1 rescue, developmental outcome scoring Cell reports High 26235619
2015 ERK1 and ERK2 regulate chondrocyte terminal differentiation; conditional knockout of ERK1/2 in hypertrophic chondrocytes (Osx-Cre) caused expanded hypertrophic zones, decreased Mmp13 and Osteopontin, and downregulation of Egr1/Egr2 transcription factors; MEK1-ERK signaling activates the Osteopontin promoter in part through Egr1 and Egr2. Conditional knockout (Osx-Cre), histology, in situ hybridization, qRT-PCR, transient transfection reporter assays Journal of bone and mineral research High 25401279
2015 ERK1 regulates hematopoietic stem cell niches by controlling osteoclastogenesis through M-CSF receptor (M-CSFR) expression on myeloid progenitors; ERK1-deficient mice show mild osteopetrosis, impaired HSC lodging and homing, reduced GMP frequency, and decreased M-CSFR expression on hematopoietic progenitors upstream of osteoclasts. ERK1 knockout mice, serial bone marrow transplantation, flow cytometry, in vitro and in vivo osteoclastogenesis assay, Western blot (M-CSFR expression) PloS one Medium 22303456
2017 ERK1/2 phosphorylates INTS11, the catalytic subunit of the Integrator complex, following EGF stimulation; activated ERK1/2 is recruited to immediate early genes at their promoters; Integrator is required to transduce ERK1/2 transcriptional responses at immediate early genes and their enhancers. Pharmacological ERK inhibition, ChIP-seq, Integrator subunit depletion, phosphorylation assays, cancer cell growth assays Genes & development Medium 28982763
2017 HDAC6 deacetylates ERK1 at Lys-72 to stimulate its activity; CBP and p300 acetyltransferases acetylate ERK1; acetylation-mimicking mutation K72Q reduces ERK1 phosphorylation and enzymatic activity in vitro toward ELK1; ERK1 and HDAC6 form a positive feed-forward loop (ERK1 phosphorylates HDAC6 to increase its deacetylase activity, and HDAC6 deacetylates ERK1 to increase its kinase activity). Co-IP, HDAC6 knockdown, HDAC inhibitor treatment, site-directed mutagenesis (K72Q, K72R), in vitro kinase assay (ELK1 substrate), mass spectrometry (acetylation site identification), luciferase reporter assay The Journal of biological chemistry High 29259132
2015 SUV420H1 trimethylates ERK1 at Lys-302 and Lys-361; substitution of these methylation sites diminishes ERK1 phosphorylation; SUV420H1 knockdown reduces phospho-ERK1, total ERK1 protein, and ERK1 transcript levels. In vitro methylation assay, site-directed mutagenesis (K302/K361), SUV420H1 knockdown, Western blot, qRT-PCR Oncotarget Medium 26586479
2015 ERK1/2 can feedback-regulate MEK1/2 levels: ERK1/2 activity upregulates MEK1 at the transcriptional level and downregulates MEK2 at the post-translational level via the proteasome; ERK1/2 knockdown abrogates both regulations. ΔRaf-1:ER and B-Raf(V600E) inducible systems, ERK1/2 siRNA knockdown, qPCR, luciferase promoter and 3'UTR reporters, proteasome inhibitors (MG132, bortezomib), Western blot Cellular signalling Medium 26163823
2015 Transient pharmacological inhibition of MAPK3/1 (with PD0325901) abolishes LH/hCG-induced ovulation in mice; MAPK3/1 regulates ovulation at least in part through transcriptional induction of Egr1, which binds to and activates the Ptgs2 (COX-2) promoter in granulosa cells. In vivo pharmacological inhibition, ChIP assay (Egr1 binding to Ptgs2 promoter), Egr1 siRNA knockdown in primary granulosa cells, qRT-PCR, ovulation counting PloS one High 25803847
2017 MAPK3/1 participates in primordial follicle activation through mTORC1-KITL signaling in pre-granulosa cells; inhibition of MAPK3/1 with U0126 reduces follicle activation and decreases phosphorylation of Tsc2, S6K1, and rpS6 (mTORC1 targets) and KITL expression, and also decreases Akt phosphorylation and Foxo3 nuclear export in oocytes. Ex vivo ovary culture, pharmacological inhibition (U0126), Western blot, immunofluorescence Journal of cellular physiology Medium 28218391
2019 ERK1/2 loss in quiescent adult endothelium (endothelial Erk2 knockout on Erk1-null background) causes hypertension, decreased eNOS expression, increased endothelin-1, widespread endothelial-to-mesenchymal transition (EndMT) via TGFβ signaling, fibrosis, and death; ERK1/2 signaling is required to suppress TGFβ pathway and maintain endothelial identity. Conditional knockout (endothelial-specific Erk2 deletion on Erk1-/- background), endothelial fate mapping, immunostaining, RNA-seq, HUVEC in vitro knockdown, computational causal modeling The Journal of experimental medicine High 31196980
2019 Erk1/2 directly phosphorylate FGF receptor 1 (FGFR1) at a specific serine residue and multiple threonine residues in FRS2, substantially reducing tyrosine phosphorylation of FGFR1 and its downstream signaling; simultaneous inhibition of both Erk1/2 and p38 kinase leads to prolonged FGFR1/FRS2 tyrosine phosphorylation, revealing a crosstalk between p38 and Erk1/2 in negative feedback of FGF signaling. Pharmacological inhibition (ERK and p38 inhibitors), phospho-Western blot, anisomycin p38 activation, stable cell lines (FGFR1-expressing NIH3T3 and U2OS) International journal of molecular sciences Medium 31013829
2017 S-nitrosylation of ERK1 at Cys183 inhibits ERK1/2 phosphorylation and promotes glioma cell apoptosis; C183A mutation (preventing S-nitrosylation) partially reverses NO donor-induced reductions in cell viability and ERK1/2 phosphorylation; inverse correlation between S-nitrosylation and phosphorylation was confirmed in human glioma tissues. Biotin switch assay, site-directed mutagenesis (C183A), Western blot, flow cytometry (apoptosis), cell viability assay, NO donor treatment International journal of molecular medicines Medium 29286066
1998 Region-specific subcellular localization of activated p42/p44MAPK determines their functional targets in vivo: in hippocampal neurons after ECS, activated MAPKs are cytoplasmic and phosphorylate cytoplasmic substrate MAP2c but not nuclear c-Fos; in cortical neurons, activated MAPKs localize to both nucleus and cytoplasm and phosphorylate both MAP2c and c-Fos. In vivo electroconvulsive shock, immunohistochemistry (phospho-MAPK), pharmacological inhibition (PD098059), immunoblot for MAP2c phosphorylation, c-Fos immunohistochemistry Journal of neurochemistry Medium 9453550
2009 ERK-1 kinase activity prevents TNF+cycloheximide-induced apoptosis through phosphorylation of Bad and inhibition of Bax translocation to mitochondria, thereby preventing cytochrome c release; a kinase-dead ERK-1 (K71R) sensitizes cells to apoptosis; these effects are mediated through the intrinsic mitochondrial pathway. ERK-1 and K71R kinase-dead overexpression in HeLa cells, Western blot (Bad phosphorylation, Bax, Bcl-2, cytochrome c), cell death assay, caspase inhibitor experiments Journal of cellular biochemistry Medium 19777442

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 ERK1/2 MAP kinases: structure, function, and regulation. Pharmacological research 1275 22569528
1996 Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. The Journal of biological chemistry 1110 8702807
1993 Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proceedings of the National Academy of Sciences of the United States of America 965 8397401
1993 Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. The Journal of cell biology 621 8394845
2009 MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. Science (New York, N.Y.) 522 19443782
2003 Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. The EMBO journal 473 14532121
2016 Negative feedback regulation of the ERK1/2 MAPK pathway. Cellular and molecular life sciences : CMLS 421 27342992
2008 Tumour cell survival signalling by the ERK1/2 pathway. Cell death and differentiation 419 18846109
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2006 MAPK signalling: ERK5 versus ERK1/2. EMBO reports 333 16880823
1997 The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42/p44MAPK cascade. The Journal of biological chemistry 318 8995446
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1995 Transforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells. The Journal of biological chemistry 283 7706248
2005 The role of erk1 and erk2 in multiple stages of T cell development. Immunity 280 16226508
1995 Matrix/integrin interaction activates the mitogen-activated protein kinase, p44erk-1 and p42erk-2. The Journal of biological chemistry 260 7814385
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2004 Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses. Nature medicine 186 15107845
1993 Differential activation of p44mapk (ERK1) by alpha-thrombin and thrombin-receptor peptide agonist. The Biochemical journal 167 8380983
2005 ERK1/2 regulates epidermal chemokine expression and skin inflammation. Journal of immunology (Baltimore, Md. : 1950) 164 15814736
1992 Functional expression and growth factor activation of an epitope-tagged p44 mitogen-activated protein kinase, p44mapk. Molecular biology of the cell 159 1372523
2002 Early activation of the p42/p44MAPK pathway mediates adenosine-induced nitric oxide production in human endothelial cells: a novel calcium-insensitive mechanism. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 145 12374781
1995 Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. Blood 142 7579336
2018 ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway. Pharmacology & therapeutics 138 29454854
2004 Xenoestrogen-induced ERK-1 and ERK-2 activation via multiple membrane-initiated signaling pathways. Environmental health perspectives 137 15531431
2022 ERK1/2 in immune signalling. Biochemical Society transactions 134 36281999
2007 17beta-estradiol induces the translocation of the estrogen receptors ESR1 and ESR2 to the cell membrane, MAPK3/1 phosphorylation and proliferation of cultured immature rat Sertoli cells. Biology of reproduction 128 17928626
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2010 ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish. The Journal of clinical investigation 120 20237411
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2018 Mechanisms shaping the role of ERK1/2 in cellular senescence (Review). Molecular medicine reports 109 30535440
2012 PTEN regulation of ERK1/2 signaling in cancer. Journal of receptor and signal transduction research 94 22737980
2012 Mechanisms of acquired resistance to ERK1/2 pathway inhibitors. Oncogene 93 22562245
2009 Total ERK1/2 activity regulates cell proliferation. Cell cycle (Georgetown, Tex.) 90 19242111
2002 Enhanced ERK-1/2 activation in mice susceptible to coxsackievirus-induced myocarditis. The Journal of clinical investigation 90 12070303
1996 Calcium-dependent activation of Erk-1 and Erk-2 after hypo-osmotic astrocyte swelling. The Biochemical journal 89 8947482
2008 Activation of Erk1/2 and Akt following unilateral ureteral obstruction. Kidney international 84 18449171
1995 Cell cycle reentry of mammalian fibroblasts is accompanied by the sustained activation of p44mapk and p42mapk isoforms in the G1 phase and their inactivation at the G1/S transition. Journal of cellular physiology 83 7775600
2015 Functional Redundancy of ERK1 and ERK2 MAP Kinases during Development. Cell reports 82 26235619
2014 Interaction of mTOR and Erk1/2 signaling to regulate oligodendrocyte differentiation. Glia 82 25060812
1996 Age-related reductions in the activation of mitogen-activated protein kinases p44mapk/ERK1 and p42mapk/ERK2 in human T cells stimulated via ligation of the T cell receptor complex. Cellular immunology 78 8640866
1993 Molecular cloning, expression, and characterization of the human mitogen-activated protein kinase p44erk1. Molecular and cellular biology 76 7687743
2023 Navigating the ERK1/2 MAPK Cascade. Biomolecules 75 37892237
2017 MAPK3/1 participates in the activation of primordial follicles through mTORC1-KITL signaling. Journal of cellular physiology 74 28218391
2007 AKT and ERK1/2 signaling in intrahepatic cholangiocarcinoma. World journal of gastroenterology 73 18161916
2019 Comprehensive Analysis of ERK1/2 Substrates for Potential Combination Immunotherapies. Trends in pharmacological sciences 68 31662208
2015 ERK1 and ERK2 regulate chondrocyte terminal differentiation during endochondral bone formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 62 25401279
2017 Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3 Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying. Gastroenterology 59 28438610
2014 Erk1/2 activation and modulation of STAT3 signaling in oral cancer. Oncology reports 59 25174327
2021 Cannabidiol induces autophagy via ERK1/2 activation in neural cells. Scientific reports 57 33686185
2005 Cdc42 downregulates MMP-1 expression by inhibiting the ERK1/2 pathway. Journal of cell science 57 15728253
2019 Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium. The Journal of experimental medicine 56 31196980
2006 AsialoGM1 and TLR5 cooperate in flagellin-induced nucleotide signaling to activate Erk1/2. American journal of respiratory cell and molecular biology 56 16439799
2008 CTGF is increased in basal deposits and regulates matrix production through the ERK (p42/p44mapk) MAPK and the p38 MAPK signaling pathways. Investigative ophthalmology & visual science 50 19011018
1998 Region-specific targets of p42/p44MAPK signaling in rat brain. Journal of neurochemistry 50 9453550
2009 Effect of PD98059, a selective MAPK3/MAPK1 inhibitor, on acute lung injury in mice. International journal of immunopathology and pharmacology 49 20074457
2017 ERK1 and ERK2 activation modulates diet-induced obesity in mice. Biochimie 48 28302472
2007 ERK 1/2 signaling pathway is involved in nicotine-mediated neuroprotection in spinal cord neurons. Journal of cellular biochemistry 48 16888810
2017 Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs. Genes & development 45 28982763
2018 Importance of ERK1/2 in Regulation of Protein Translation during Oocyte Meiosis. International journal of molecular sciences 44 29494492
2015 Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis. Redox biology 44 26202867
2007 RGS protein specificity towards Gq- and Gi/o-mediated ERK 1/2 and Akt activation, in vitro. Journal of biochemistry and molecular biology 44 18047785
2010 The DSCs-expressed CD82 controls the invasiveness of trophoblast cells via integrinbeta1/MAPK/MAPK3/1 signaling pathway in human first-trimester pregnancy. Biology of reproduction 43 20075392
2012 The release of EGF domain from EGF-like factors by a specific cleavage enzyme activates the EGFR-MAPK3/1 pathway in both granulosa cells and cumulus cells during the ovulation process. The Journal of reproduction and development 42 23124701
2010 Anaplasma phagocytophilum AptA modulates Erk1/2 signalling. Cellular microbiology 41 20716207
2009 Thioredoxin regulates cell cycle via the ERK1/2-cyclin D1 pathway. Antioxidants & redox signaling 41 19622016
2015 ERK1 and ERK2 present functional redundancy in tetrapods despite higher evolution rate of ERK1. BMC evolutionary biology 40 26336084
2014 Linear B-cell epitope mapping of MAPK3 and MAPK4 from Leishmania braziliensis: implications for the serodiagnosis of human and canine leishmaniasis. Applied microbiology and biotechnology 40 25359475
2000 Sphingosine 1-phosphate activates Erk-1/-2 by transactivating epidermal growth factor receptor in rat-2 cells. IUBMB life 38 11185956
2017 Histone deacetylase 6 (HDAC6) deacetylates extracellular signal-regulated kinase 1 (ERK1) and thereby stimulates ERK1 activity. The Journal of biological chemistry 37 29259132
2006 Role of tyrosine kinase receptors in angiotensin II AT2 receptor signaling: involvement in neurite outgrowth and in p42/p44mapk activation in NG108-15 cells. Endocrinology 37 16809450
2021 ERK1/2: An Integrator of Signals That Alters Cardiac Homeostasis and Growth. Biology 36 33923899
2006 Mechanisms of ERK1/2 regulation by seven-transmembrane-domain receptors. Current pharmaceutical design 34 16712482
2017 Effects of ERK1/2 S-nitrosylation on ERK1/2 phosphorylation and cell survival in glioma cells. International journal of molecular medicine 33 29286066
2015 Effect of the transient pharmacological inhibition of Mapk3/1 pathway on ovulation in mice. PloS one 31 25803847
2017 MicroRNA-15b deteriorates hypoxia/reoxygenation-induced cardiomyocyte apoptosis by downregulating Bcl-2 and MAPK3. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 29 28814571
2017 GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis. Biochemical and biophysical research communications 28 29128363
2015 Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis. Oncotarget 28 26516701
2022 The role of ERK-1 and ERK-2 gene polymorphisms in PCOS pathogenesis. Reproductive biology and endocrinology : RB&E 27 35768803
2021 Cryptotanshinone Attenuates Ischemia/Reperfusion-induced Apoptosis in Myocardium by Upregulating MAPK3. Journal of cardiovascular pharmacology 27 33662979
2019 Human peroxidasin 1 promotes angiogenesis through ERK1/2, Akt, and FAK pathways. Cardiovascular research 27 29982533
2015 SUV420H1 enhances the phosphorylation and transcription of ERK1 in cancer cells. Oncotarget 27 26586479
2015 Neuropeptide Y receptor mediates activation of ERK1/2 via transactivation of the IGF receptor. Cellular signalling 26 25817573
2009 ERK-1 MAP kinase prevents TNF-induced apoptosis through bad phosphorylation and inhibition of Bax translocation in HeLa Cells. Journal of cellular biochemistry 26 19777442
2024 ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2. Redox biology 25 38581859
2020 JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction. Cell death and differentiation 25 32346136
2019 Biological Effects of Shikonin in Human Gingival Fibroblasts via ERK 1/2 Signaling Pathway. Molecules (Basel, Switzerland) 25 31574951
2014 Functional status of STAT3 and MAPK3/1 signaling pathways in granulosa cells during bovine follicular deviation. Theriogenology 25 25442017
2023 Flavonoids as Strong Inhibitors of MAPK3: A Computational Drug Discovery Approach. International journal of analytical chemistry 24 37090055
2020 PARK7 enhances antioxidative-stress processes of BMSCs via the ERK1/2 pathway. Journal of cellular biochemistry 24 32918333
2021 The Role of MAPK3/1 and AKT in the Acquisition of High Meiotic and Developmental Competence of Porcine Oocytes Cultured In Vitro in FLI Medium. International journal of molecular sciences 22 34681809
2015 Both ERK1 and ERK2 are required for enterovirus 71 (EV71) efficient replication. Viruses 22 25803100
2015 ERK1/2 can feedback-regulate cellular MEK1/2 levels. Cellular signalling 22 26163823
2006 PI3K and ERK 1-2 regulate early stages during head regeneration in hydra. Development, growth & differentiation 22 16512856
2006 Amyloid precursor protein modulates ERK-1 and -2 signaling. Annals of the New York Academy of Sciences 21 17384289
2020 Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin. JCI insight 20 32841221
2019 Crosstalk between p38 and Erk 1/2 in Downregulation of FGF1-Induced Signaling. International journal of molecular sciences 19 31013829
2019 Isoform-Specific Roles of ERK1 and ERK2 in Arteriogenesis. Cells 19 31877781
2012 ERK1 regulates the hematopoietic stem cell niches. PloS one 19 22303456

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